There have been great advances in understanding the immunologic mechanisms of Type 1 diabetes (T1D) but these advances have not translated into new therapies for the disease. The results of recent ?successful? trials have shown transient improvement in insulin secretion but sustained improvement has not been uniformly seen. The basis for this proposal is that the successful development of an immune therapy requires addressing the metabolic impairment as well. This R34 planning grant is to design and complete the administrative and other tasks needed to commence a randomized Phase II clinical trial to compare the combination of teplizumab (a non-FcR binding anti-CD3 mAb) with Bydureon (extended release exenatide) to either drug alone in patients with new onset T1D. Teplizumab has been shown, in 4 randomized controlled clinical trials, to improve C- peptide responses in patients with new and recent onset T1D. In previous studies, we have identified immunologic mechanisms that are associated with clinical responses, involving modulation of the CD8+ T cell compartment. In addition, we found that the drug causes migration of T cells to the gut and acquisition of regulatory function. Bydureon, the GLP-1 receptor agonist, is approved for treatment of T2D. Its mechanisms of action target dysfunctional features of T1D. It inhibits glucagon levels, slows gastric emptying, stimulates insulin release, and has been postulated to stimulate beta cell replication. It also may have anti-inflammatory effects. Short term use of exenatide has been shown to have dramatic effects reducing post-prandial glucose excursions. The primary endpoint of the proposed trial is to test whether the combination of teplizumab + Bydureon is more effective than either drug alone in inducing clinical remission defined as a HbA1c< 7.0% and insulin use < 0.25U/kg/d: These parameters were chosen based on ADA standards of care the analysis of previous clinical trials. The secondary endpoints including a comparison of C-peptide responses in the treatment arms, the frequency of insulin independent remissions, and glycemic excursion. An important part of the proposed studies is to build on our previous studies and those from collaborative work with the ITN to identify the basis for immunologic responses. We will expand our studies of the gene signatures found in clinical responders and the changes in diabetes antigen specific CD8+ T cells as well as the rates of ? cell killing. In addition, we will test the novel hypothesis that the microbiome modulates responses to teplizumab which has been suggested by our studies in humanized mice. This clinical trial proposal is unique because it is the first that addresses two relevant disease mechanisms. It also uses, as endpoints, measurements that are likely to be widely accepted and enable the development of treatments that will improve the clinical condition for patients.